Life's Greatest Secret

by Matthew Cobb

  There is something missing from this description of protein synthesis. In many cases – perhaps most, perhaps almost all – protein synthesis involves the presence of molecular chaperones, which alter the rate of folding.43 These chaperones can be molecules such as the heat shock proteins that prevent polypeptide chains from clumping together, or they may block competing biochemical reactions during the folding process. Chaperones can equally be hollow molecules that provide a favourable chemical micro-environment for the protein to be correctly folded, within a space known by the sci-fi-sounding term Anfinsen’s cage – named after Christian Anfinsen, who won the 1972 Nobel Prize in Chemistry for his work showing the link between the one-dimensional amino acid sequence and the three-dimensional protein structure.44

  In a 1970 letter to Howard Temin, Crick, open-minded as ever, showed that he recognised the possibility that other factors apart from the amino acid sequence might determine three-dimensional protein structure: ‘I do not subscribe to the view that all “information” is necessarily located in nucleic acids. The central dogma only applies to residue-by-residue sequence information.’45

  Crick would no doubt have been intrigued but unworried by some aspects of protein synthesis that might appear to contradict the central dogma. In a large number of bacteria and some eukaryotes such as fungi, some peptides are assembled without the direct involvement of DNA, mRNA or ribosomes. The existence of these oddities does not go against the key argument of the central dogma, because there is no route for information to flow from the protein into DNA. Instead, non-ribosomal peptides raise the question of how the information they contain is represented and transmitted genetically, if it is not contained in a nucleic acid sequence. There are two linked answers. Non-ribosomal peptides are synthesised using an assembly line of enzymes and the order of the amino acids is determined by the order in which the enzymes act on the growing chain – each functional part of each enzyme adds a particular amino acid. However, these enzymes are themselves encoded by genes, so ultimately the information that represents the peptide’s amino acid sequence is in fact contained in DNA sequences, albeit indirectly.46

  At the beginning of 2015, a protein called Rqc2p was discovered that actually gets involved in ribosomal protein synthesis, and recruits tRNA molecules to add two kinds of amino acid – alanine and threonine – to the end of a protein chain when synthesis gets stalled.47 By adding a number of these two amino acids in what seems to be a random order, Rqc2p appears to mark the protein (or perhaps the ribosome) for imminent destruction by the cell’s house-keeping machinery. The order of the two amino acids does not seem to be important, and they are not added in any consistent sequence, so, strictly speaking, this example does not contradict Crick’s hypothesis that a protein cannot determine the amino acid sequence of another protein. However, it represents a step towards that possibility. Other odd examples may yet be discovered – as Crick emphasised in 1970, our knowledge is still far too incomplete for us to assert that our current understanding is completely correct. It explains what we have so far discovered, but we may find there are further surprises.

  For some philosophers of science, the role of chaperones and the potential existence of information outside the genetic code undermines Crick’s 1957 assumption that protein folding is a spontaneous, self-directed phenomenon. Some even argue that proteins are an agency of heredity, opening the door to the inheritance of acquired characteristics.48 These are very much minority views among philosophers – and even more so among scientists. The role of chaperones is simply what their metaphorical name suggests: they protect and facilitate interactions that lead to three-dimensional protein structure; they do not actively guide and structure them. And even if it eventually turns out that some proteins do directly form the three-dimensional structure of certain proteins (as with prions), the wealth of existing data about protein synthesis indicates that these will be minor curiosities, exceptions that prove the rule.49

  *

  Some readers – and in particular any philosophers out there – may be uneasy with the way in which findings that do not conform to the central dogma seem to have been dismissed as exceptions or the products of pathology, thereby apparently leaving the fundamental argument intact when in reality it has been severely weakened. Apart from the fact that none of these examples provides evidence for the transfer of information from protein → DNA, this relaxed attitude, which I share with the vast majority of biologists, underlines a difference between general statements or hypotheses in biology and axioms or laws in mathematics or physics. A single example of a particle travelling faster than light would require a great deal of work by theoretical physicists in order to reshape our understanding of the Universe. In contrast, a solid example of information flowing directly from protein → DNA would not cause a radical revision of our concepts of how genetics and evolution work, unless it was discovered that such transfers take place systematically and on a wide scale.

  Were such an example to be discovered, that part of the central dogma would no longer be true, and it is possible that new technologies would become available for manipulating organisms. But virtually all of our existing results and experimental protocols would almost certainly emerge unscathed, because they have been shown to function perfectly well in the absence of such an additional mode of information transfer. The challenge would be for scientists to put the new exception into the existing framework, explaining it in the historical and evolutionary context of the central dogma. If that were not possible, then a radically new explanation would be necessary, and the central dogma would be relegated to the status of an abandoned fruitful hypothesis, an idea that led to successful and informative experimental work, but which was ultimately shown to be wrong.

  This would not constitute some kind of moral or philosophical victory for the epigenetic revolutionaries: the reason that scientists accept the central dogma is not because it is a dogma but because the evidence supports it. If new evidence were to arise, then, as the French phrase puts it: Il n’y a que les imbéciles qui ne changent pas d’avis – only fools do not change their mind.

  * ‘Epigenetics’ sounds much more exciting than ‘gene regulation’, which is no doubt why the term is increasingly being used.

  –FOURTEEN–

  BRAVE NEW WORLD

  In 2010, the molecular geneticist and entrepreneur Craig Venter hit the headlines. In an article published in Science, his group claimed they had created the world’s first synthetic organism.1 More than a decade earlier, Venter’s group began to study the bacterium Mycoplasma mycoides, which causes lung disease in ruminants. Over years of painstaking work, they succeeded in creating a synthetic version of the M. mycoides genome, having disarmed various pathogenic genes. They then introduced the synthetic DNA chromosome – over a million base-pairs long – into a cell of a related species from which the genomic DNA had been removed. Once installed in its new host, the M. mycoides genome was able to function successfully, controlling the cell and reproducing. A new life-form had appeared, created through the work of scientists.

  This feat had two important limitations. First, the cell they used was not empty: it contained all the natural cellular machinery, such as ribosomes, metabolites and enzymes, needed for the synthetic DNA to make the new organism function. These vital ingredients had not been touched by Venter’s group. Second, the DNA they introduced into that cell had not been written from scratch; it was copied from the genome of an existing organism. Despite all the human ingenuity involved, the success of the project relied fundamentally on work that had already been done over hundreds of millions of years by natural selection in creating the cell and its contents and in encoding the genome.

  Nevertheless, in typical entrepreneurial fashion, the researchers from the J. Craig Venter Institute stamped their ownership on the new bacterium – called Mycoplasma mycoides JCVI-syn1.0 – in the shape of genetic watermarks. Using a complex code made up of combinations of letters from the genetic code, the
Venter group hid several identifying marks in the DNA sequence of their creation. These included three quotations (one from A Portrait of the Artist as a Young Man was briefly the subject of a humourless legal action by the James Joyce estate), the names of forty-six people who were involved in the work, and an address to which e-mails could be sent by anyone able to crack the code. The first correct solution was received a little more than three hours after the watermark sequence went on line.2

  In a 2012 lecture in Dublin to commemorate Schrödinger’s What is Life?, Venter suggested that he could use his technique to teleport life-forms from the surface of Mars. He proposed sending a robot to the Red Planet that could sequence Martian DNA (assuming that Martians contain DNA) and then transmit the sequence back to Earth. We could then reassemble the Martian in a laboratory, using the technique employed to create Mycoplasma mycoides JCVI-syn1.0.3 The idea of transmitting Martians caused some excitement in the press (‘Geneticist aims to teleport Mars life back to Earth’, said The Boston Globe) even though Venter did not even invent the idea of teleporting genes – Norbert Wiener first proposed this method for transmitting an organism through the ether in his 1950 book The Human Use of Human Beings.

  As Venter points out, recreating a Martian in a maximum-containment facility on Earth would be safer than bringing it hurtling back through the atmosphere, with the potential of a crash and the pollution of the planet. There are some difficulties, however. If there were life on Mars, it would be very surprising if a Martian genome were able to pop into an Earthling cell and just start working – the cellular context would almost certainly be utterly different from that required by the Martian DNA. In the extremely unlikely event that a Martian was found, that it was based on DNA and that it could kickstart itself into life in an Earthling cell, recreating it on Earth would show that the Earthling and Martian branches of life shared a common ancestor. The most probable explanation would be that the Martian microbe came from Earth, blasted into space on a lump of rock after a meteorite strike and eventually plummeting onto the Red Planet. If there is life on Mars that is truly Martian, it seems highly unlikely it is similar to Earth life. There is no reason to imagine that DNA is the only possible informational molecule; in fact, our deep evolutionary past, and the ingenuity of today’s scientists, both show that is not the case.

  *

  Biotechnology is not a recent development. For thousands of years, humanity has used the power of microbes to produce two foodstuffs that are seen as an essential part of everyday life for much of the planet: bread and beer. Both rely on harnessing the respiratory mechanisms of yeast to produce carbon dioxide (which makes bread rise) and alcohol (which makes beer intoxicating). What was initially a blind process has been utterly transformed over the past four decades, as modern biotechnology has exploited our ability to manipulate the genetic code to create organisms containing new genes, including genes from other species.4 New terms have been coined – biotechnology, genetic engineering, synthetic biology – but they all ultimately describe the use of genetic manipulation to alter living organisms.5

  Many drugs, including hormones, are now produced by harnessing the power of genetic engineering, involving the insertion of the relevant gene into a microbe that then churns out the desired material. Some examples are frankly bizarre, such as the goats that express a spider gene for producing silk, and excrete the stuff in their milk.6 If the spider-goats can produce sufficient quantities of the strong and flexible silk, new products such as stab-proof jackets could be created. Looking to the future, research groups around the world are trying to address the two central problems facing our species – energy and food supplies – by manipulating cells to produce fuel and meat.

  Over the past couple of decades, genetically modified (GM) plants have become widespread in agriculture, in particular in the US. In 2014, 94 per cent of US soybean crops were GM, as were 93 per cent of corn crops, 95 per cent of sugar beet crops and 96 per cent of cotton.7 Some of these crops are pest-resistant because they have been engineered to produce a natural insecticide that is normally produced by the soil bacterium Bacillus thuringiensis (these are therefore known as Bt crops). Other crops are herbicide-resistant and enable farmers to increase yield by reducing the need to leave space for weeding – more plants can be grown per acre.

  The best-known GM crop is the Roundup Ready soybean, produced by the agrichemical company Monsanto, which resists Monsanto’s own brand of herbicide, Roundup. Despite the very real benefits of these crops in terms of higher productivity, the increased use of herbicides reinforces the bleak monoculture of much of modern industrial farming, reducing biodiversity in the immediate vicinity of the farm. Herbicides can also pollute local water sources, with unintended consequences for wildlife, in particular for amphibians.8 The safety and reliability of GM technology is not at issue here; it is the aims and consequences of its use that need to be addressed.

  When GM food crops were first introduced into the UK, the tabloid press described them as ‘Frankenfood’, and there was widespread hostility to scientific trials of new GM crops, including direct action by activists who trashed the fields. Health fears relating to the consumption of GM food have been widespread but are entirely unjustified: there is no evidence that consumption of GM organisms will do you any harm at all. Vague unease about ‘manipulating nature’ is similarly mistaken – all the food we eat has been genetically manipulated over thousands of years through artificial selection by our ancestors. The difference is simply one of method: artificial selection of our foodstuffs is merely slower and generally less effective than direct genetic manipulation.

  Even the widespread feeling that there is something unnatural about transferring genes from one species to another is unfounded. Exchange of genes between species – known as horizontal gene transfer – occurs quite readily in microbes, and sometimes in animals and plants. Very specific adaptations have appeared through horizontal gene transfer. For example, the pea aphid is the only animal in the world that can synthesise red pigments known as carotenoids (all other animals have to acquire these compounds from the environment, by eating plants). The aphid gained this ability by incorporating genes from a fungus into its genome; when, how and why this happened is unknown, but it demonstrates that horizontal gene transfer, a form of inadvertent natural genetic engineering, can also explain some adaptations of multicellular organisms.9

  A recent experimental study showed that horizontal gene transfer could help ordinary bacteria to become plant symbionts by simultaneously transferring genes involved in symbiosis and genes that led temporarily to an increased mutation rate in the bacteria. As a result, the bacteria responded rapidly to selection pressure, accelerating their transformation into symbionts.10 Horizontal transfer effects may not be limited to genes – the parasitic plant dodder exchanges not genes but mRNA with its plant host. In some circumstances even gene products can jump the species barrier.11

  Even more spectacularly, horizontal gene transfer was at the heart of the evolution of the eukaryotic lineage, which includes all multicellular organisms, along with some single-celled organisms such as yeast. As well as containing the DNA of the ancestor of the mitochondrion, our genome also plays host to many genes from prokaryotic organisms, which were transferred into our ancestors by horizontal gene transfer. We are all the product of gene transfer between species. Faced with the evidence that gene transfer between species is so widespread, no one can argue against GM technology on the basis that it is unnatural.

  *

  Some applications of genetic engineering relate to areas of technology that are neither controversial nor bizarre. By manipulating the genetic sequence, it is possible to use DNA to store information generated by humans, perhaps providing an efficient, compact and future-proofed storage system. DNA, unlike cassettes, floppy discs or VHS tapes, will not go out of date. In 2013, Ewan Birney’s group in Cambridge announced that they had written 739 kilobytes of computer data into DNA, using a code made out of g
roups of nucleotides.12 They synthesised DNA containing this encoded information, sequenced it and reconstructed the original files – these included a text file containing all of Shakespeare’s sonnets, a PDF version of Watson and Crick’s description of the double helix, an MP3 extract of Martin Luther King’s ‘I have a dream’ speech, and a JPEG image of the team’s laboratory. There was not a single error, and all the files were functional.

  The idea behind this proof of principle was to find a method that could guarantee future data storage in systems where huge amounts of data are being produced, such as at CERN, where the amount of data from the Large Hadron Collider and other experiments currently stands at more than 80 petabytes (1 petabyte (PB) = 1,000,000,000,000,000 bytes, or 1015 bytes) and is growing by at least 15 PB per year. At the moment, these data are stored on magnetic tape; DNA storage would be ideal for archiving data that rarely need to be accessed, in particular with the inevitable future decline in costs for reading and encoding DNA. Information storage in DNA is far more space-efficient than in other materials: a single 1-gram drop of DNA could store as much information as hard drives weighing around 150 kilograms. In November 2014, New York rock band OK Go announced that their new record, Hungry Ghosts, would be released on DNA as well as in the usual formats.13 Although this was clearly a stunt, it may point the way to the future: DNA-based data cannot be read as quickly as a magnetic tape, but it can be safely stored for thousands of years if kept in the right conditions. One joker has facetiously suggested that the double helix would be particularly useful for storing the wave of genetic sequence data that is being generated at an exponential rate in laboratories all over the planet.*